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Prodopaminergic Drugs for Treating the Negative Symptoms of Schizophrenia

Systematic Review and Meta-analysis of Randomized Controlled Trials

Sabe, Michel MD*; Kirschner, Matthias MD†,‡; Kaiser, Stefan MD*

Journal of Clinical Psychopharmacology: November/December 2019 - Volume 39 - Issue 6 - p 658–664
doi: 10.1097/JCP.0000000000001124
Review Articles

Background The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments.

Methods We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder.

Medline, EMBASE, and several other databases as well as trial registries were searched for placebo-controlled trials.

Results Ten randomized controlled trials were included in the meta-analysis, 6 trials on modafinil, 2 on armodafinil, 1 on L-dopa, and 1 on pramipexole. Overall, prodopaminergic agents did not significantly reduce negative symptoms. Restricting the analysis to studies requiring a minimum threshold for negative symptom severity, modafinil/armodafinil showed a significant but small effect on negative symptoms. A subset of studies allowed for calculating specific effects for the negative symptom dimensions diminished expression and amotivation, but no significant effect was found. Prodopaminergic agents did not increase positive symptom scores.

Conclusions The currently available evidence does not allow for formulating recommendations for the use of prodopaminergic agents for the treatment of negative symptoms. Nevertheless, the observed improvement in studies defining a minimum threshold for negative symptom severity in the absence of an increase in positive symptoms clearly supports further research on these agents.

From the *Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Zurich, Switzerland.

Received April 21, 2019; accepted after revision August 8, 2019.

Reprints: Michel Sabe, MD, Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, 2, Chemin du Petit-Bel-Air, CH-1226 Thonex, Switzerland (e-mail:

There was no external funding for this study.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (

Online date: October 30, 2019

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